Cyclopentanophenathreno-1, 3-oxazines



a 3,033,860 CYCLOPENTANOPHENATHRENO-1,3-XAZINES Martin Eric Kuehne,Summit, N.J., assignor to Ciba Corporation, a corporation of New JerseyNo Drawing. Filed Feb. 19, 1960, Ser. No. 9,699 i 16 Claims. (Cl.260-23955) United States Patent on; v

in which R represents aliphatic hydrocarbon or substituted aliphatichydrocarbon, R represents 0x0, functionally converted 0x0, or one of thegroups of the formulae H(H), OH(H), OH(R in which R represents a loweraliphatic hydrocarbon, OAc(H), in which Ac represents an acyl radical,or OAc(R in which Ac and R have the previously given meaning, and Rrepresents hydrogen, hydroxyl, acyloxy or lower alkyl, salts orquaternary ammonium compounds thereof, as well as process for thepreparation of such compounds thereof, as well as process for thepreparation of such compounds.

The radical R attached to the nitrogen atom of the oxazine nucleusrepresents an aliphatic hydrocarbon radical, such as, for example,alkyl, particularly lower alkyl, e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl,neopentyl and the like, alkenyl, primarily lower alkenyl,

v 2-cyclopentenyl,

3,633,869 Patented May 8, 1962 ice e.g. allyl, Z-methyl-allyl,S-methyl-allyl and the like, cycloalkyl, which contains from three toseven ring car bon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl and the like, cycloalkenyl, which contains from five toseven carbon atoms as ring members, e.g.

3-cyclopentenyl, Z-cyclohexenyl, 3- cyclohexenyl and the like,cycloalkyl-lower alkyl radicals, in which cycloalkyl contains from threeto seven carbon atoms as ring members, e.g. cyclopropylmethyl,cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl,l-cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl,l-cyclohexylethyl, Z-cyclohexyiethyl, l 'cyclohexylpropyl,3-cyclohexylpropyl and the like, cycloalkenyl-lower alkyl radicals, inwhich cycloalkenyl contains from five to seven ring carbon atoms, e.g.2-cyclopentenylrnethyl, 3 cyclopentenylmethyl, 2 (2 cyclopentyl)-ethyl,2-cyclohexenylmethyl, 3 -cyclohexenylmethyl, ,1-(3 -cyclohexenyl)-ethyl,2-(2-cyclohexenyl)- ethyl, ,3-(2 cyclohexenyl)-propyl and the like, orany other aliphatic hydrocarbon radical.

Substituted aliphatic hydrocarbon radicals are, for example, thosecarrying functional groups. Such groups are primarily attached to loweralkyl radicals, such as, for example, methyl, ethyl, 1,1-dimethyl-cthyl,n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl,n-pentyl, isopentyl, neopentyl and the like. One or more than onefunctional group may be attached to any of the positions of thealiphatic hydrocarbon, particularly lower alkyl, radical available forsubstitution.

Functional groups are, for example, carboxy groups or functionallyconverted carboxy groups, such as carbolower alkoxy, e.g. carbomethoxy,carbethoxy and the like, carbamyl, particularly N-unsubstitutedcarbamyl, N-monosubstituted carbamyl, such as N-lower alkyl-carbamyl,e.g. N-methyl-carbamyl and the like, N,N-disubstituted carbamyl, such asN,N-di-lower alkyl-carbamyl, e.g. N,N-dimethyl-carbamyl and. the like,cyano or any other functionally converted carboxy group.

Other functional groups attached to an aliphatic radical are, forexample, halogens, e.g. chloro, brorno and the like, as well as aminogroups, particularly'N,N- disubstituted amino groups, particularlyN,N-di-lower alkylamino, e.g. N,N-dimethylamino, N-ethyl-N-methylamino,N,N-diethy1amino, N,N-di-isopropylamino and the like, l-N,N-loweralkylene-imino group, in which the lower alkylene radical contains fromfour to' six carbon atoms, such as l-pyrrolidino, I-piperidino, 1-N,N-hexamethylene-imino and the like, l-N,N lower oxaalkylene-imino, inwhich oxa-alkylene contains preferably four carbon atoms, e.g.l-morpholino and the like, i

or 1-N,N-lo weraza-alkylene-imino, in which aza-alkylene contains fromfour to six carbon atoms, e.g. I-piperazino, 4-methyl-l-piperazino, andthe like, N-acylamino groups, in which acyl represents the acyl radicalof an organic carboxylic acid, for example, a lower alkanoic acid, e.g.acetic, propionic, pivalic acid and the like, acyl radicals,particularly those of organic carboxylic acids, such as lower alkanoicacid, e.g. acetic, 'propionic, butyric acid and the like, hydroxylgroups, esterfied hydroxyl, especially hydroxyl groups esterified withor ganic carboxylic acids, for example, lower aliphatic carboxylicacids, such .as lower alkanoic acids, e.g. acetic, propionic, pivalicacid and the like, etherified hydroxyl groups, represented, for example,by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethoxy,n-propyloxy, isopropyloxy, n-butyloxy and the like, or etherifiedmercapto groups, for example, aliphatic hydro: carbon-mercapto, such aslower alkyl-'mercapto, e.g. methylmercapto, ethylmercapto,n-propylmercapto, isopropylrnercapto, n-butylmercapto, isobutylmercaptoand the like, or any other functional group capable ofsubstitutingaliphatic hydrocarbon. x

Substitu ted aliphatic hydrocarbons are primarily those containingcarbocyclic aryl groups, such as inonocyclic carbocyclic aryl, e.g.phenyl or 'substituted'phenyl, or

bicyclic carbocyclic aryl, e.g. l-naphthyl or Z-naphthyl or substitutednaphthyl radicals. Such carbocyclic arylsubstituted aliphatichydrocarbon radicals may be represented primarily by monocyclic orbicyclic carbocyclic aryl-lower alkyl, such as phenyl-lower alkyl, e.g.benzyl,

l-phenylethyl, 2-phenylethyl, S-phenylpropyland the like, 1

. as well as l-napuhthylmethyl and the like, and these radicals,particularly phenyl-lower alkyl, substituted in the carbocyclic arylportion. Substituents attached to the latter are, for example, loweralkyl, e.g methyl, ethyl substituent. .Substituents attached tocarbocyclic aryl,

particularly monocyclic carbocyclic'aryl, portions may be attached toany of the available positions, whereby one or more than one of the sameor of different substituents may be present.

Additional substituents of an aliphatic hydrocarbon radical areheterocyclic aryl radicals, which are particularly attachedtolower'alkyl radicals. The heterocyclic radicals are primarilymouocyclic or bicyclic. heterocyclic aryl radicals, which may preferablycontain from five to six atoms as ring members in the heterocyclicportion, such as monocyclic mono-azacyclic aryl, such as pyrryl, e.g.Z-pyrryl and the like, pyridyl, e.g. Z- yridyl, 3-pyridyl, l-pyridyl andthe like, monocyclic diazacyclic aryl, such as pyridazinyl, e.g.3-pyridazinyl and the like, pyrimidyl, e.g. Z-pyrirnidyl, 4-pyrimidyland the like, pyrazinyl, e.g. 2-pyrazinyl and the like, bicyclicmono-azacyclic aryl, such as quinolyl, e.g. Z-quinolyl, 4-quinolyl, andthe like, or isoquiuolyheg. l-isoquinolyl and the like, monocyclicmonothiacyclic aryl, such as thienyl, e.g. Z-thienyl and e.gjmethyl,ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like,orhalogeno, e.g. fluoro, chloro, bromo, and the like.

, methacrylic, undecylenic acid and the like, alkynoic, such e.g.trifluoromethyl and the like, or any other suitable bonic acids, e.g.methoxy-carbonic, ethoxy-carbonic acid and the like, amino-carbonicacids (or carbamic acids), such as carbamic, N-lower alkyl-carbamicacid, e.g. N- rnethyl-carbamic and theglike, N,N-di-lower alkyl-carbamicacid, eg, N,N-dimethyl-carbamic and the like, N- carbocyclicaryl-carbamicacid, such as N-monocyclic or N-bicyclic' carbocyclicaryl-carbamic acid, e.g. N-phenylcarbamic, N-Zmaphthyl-carbamic acid andthe like, alkanoic, particularly lower alkanoic, acids, e.g. (formic,acetic,propionic, butyric, pivalic, heptanoic acid and the like,alkenoic, such as lower 'alkenoic, acids,-e.g. acrylic,

as lower alkynoic, acids, e.g.propiolic acid and the like, alkane, suchas lower alkan'e, dicarboxylic acids, e.g. succinic, glutaric acid andthe like, cycloalkane .carboxylic acids, e.g. cyclohexane carboxylicacid and the like, or

,cycloalkyl-lower alkanoic .acids, e.g. B-cyclopentyl-propicnic,cyclohexylacetic acid and the like. Acyl radicals may also be those ofsubstituted lower alkanoic acids, such as, for example, haloge'no-loweralkanoic acids, e.g. chloroacetic, dichloroacetic, trifluoroace tic,trichloroacetic acid and the like, lower alkoxy-lower alkanoic acids,

e.g. methoxyacetic acid and the like, or amino-lower alkanoic acids,particularly N,N.-di-lower alkyl-aminolower alkanoic acids, e.g.N,N-dimethylamino-acetic, 3- N,N-diethylamino-propionic acid and thelike, or N,N-

' alkylene-imiuo-lower alkanoic acids, e.g. 3-(1-piperidino)- Vpropionic acid and the like.

-the like, or mouocyclic mono-oxacyclic aryl, such as furyl,

Apart from representing two hydrogen atoms, the group R attachedto thel7-position of the steroid portion of the molecule, represents an OX0group or a functionally converted OX0 group; the'latter type may berepresented by an oxime of the formula =N-OH or =N-OAc,

in which Ac represents acyl, more specifically defined hereinbelow,v asemicarbazone of the formula V N-NHCO NH a thiosemicarbazone of theformula =NNH-CS -NH 7 Other acyl radicals maybe those of carbocyclicaryl carboxylic acids, especially monocyclic carbocyclic-aryl carboxylicacids, e.g. benzoic, 4-methyl-benzoic, .4-methoxy-benzoic,3,4,5-trimethoxy- .benzoic, 4-0-ethoxy-carbonyl-syringic,3,4-dichloro-ben zoic, 3-nitro-benzoic, 3-N,Ndimethylamino-benzoic acidand the like, or bicyclic aryl carboxylic acids, e.g. l-naphthoic,Z-naphthoic acid and the like, carbocyclic aryl-lower aliphaticcarboxylic acids, such as-monocyclic carbocyclic aryl-lower alkanoicacids, e.g. phenylacetic, diphenylacetic, 3-phenyl-propionic,4-methoxyphenylacetic acid and the like, or nionocyclic carbocyclicaryl-lower alkenoic acids, e.g. cinnamic, 4-chloro-cinnarm'c,3,4,5-trimethoxybenzoic acid and the like, heterocyclic aryl carboxylicacids, such as .monocyclic heterocyclic aryl carboxylic acids, e.g.nicotinic, isonicotinic, Z-furoic, Z-thienoic acid and the like, orheterocyclic aryl-lower aliphatic carboxylic acids, such as-rnonocyclicheterocyclic aryl-lower alkanoic acids, e.g. Z-pyridyl-acetic,Z-thienyl-acetic acid and the like.

Lower aliphatic hydrocarbon radicals representingthe group R areprimarily represented by lower alkyl, e.g. methyl, ethyl, n-propyl,isopropyl and the like, lower alkenyl, such as vinylic lower alkenyl,e.g. vinyl, 1-

propenyl and the like, or allylic lower'alkenyl, e.g. allyl,

Z-methyl-allyl, Z-butenyl and the like, for lower alkynyl, e.g. ethynyl,lj-propy'n'ylandthe like.

The group R represents hydrogen, hydroxy, functionally convertedhydroxy, particularly esterified hydroxy of the formula OAc, in which Achas the above-given meaning, or lower alkyl, e.g. methyl, ethyl and thelike.

The radical R may also stand for OH(H), outta in'which R represents analiphatic hydrocarbon, particularly a lower aliphatic hydrocarbon,radical, especially lower alkyl, lower alkenyl or lower alkynyl, to bedefined hereiubelow, OAc(H), in which Ac represents an acyl radical,particularly the acyl radical of an organic car- .boXylic acid tobedefined more specifically hereinbelow, or ()ActfR in which Ac and R havethe previously given meaning.

The acyl radical Ac in the above formulae stands particularly for theacyl radical of a therapeutically acceptable organic carboxylic acidcontaining from one to' twelve carbon atoms. Such acids may berepresented by aliphatic carbcxylic acids, such as lower alkoxy-car-Salts of the .cornpoundsof this invention are particularlytherapeutically acceptable acid addition salts with inorganic acids,particularly mineral acids, e.g. hydrochloric, hydrobromic,-sulfuriqphospho'ric acids and the like, with organic carboxylic acids,e.g. formic, acetic, propionic, glycoiic, lactic, pyruvic, malonic,succinic, maleic, hydroxymaleic, dihydroxymaleic, furnaric, rnalic,tartaric, citric, benzoic, cinna-mic, maudelic, salicylic, 4amino'salicylic, Z-phenoxybenzdic, 2-acetoxybenzoic, and the like, ororganic sulfonic acids, e.g. methane sulfonic,

ethane sulfonic,.hydroxyethane sulfonic, p-toluene sulfonic acid and thelike.

Quaternary ammonium derivatives of the compounds of this invention areparticularly lower alkyl quaternary ammoniurnsaltssuchas those withlower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride,bro-.

s,oss,seo

mide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethylsulfate, diethyl sulfate and the like, lower alkyl lower alkanesulfonates, e.g. methyl or ethyl methane or ethane sulfonate and thelike, lower alkyl lower hydroxyalkane sulfonates, e.g. methylZ-hydroxyethane sulfonate and the like, lower alkyl monocycliccarbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate and thelike. Also included as quaternary ammonium compounds are lower alkylquaternary ammonium compounds with other inorganic or organic acids,such as with those described hereinbefore as being suitable for thepreparation of acid addition salts.

Compounds of the present invention have estrogenic or uterotrophiceffects, which are manifested in growth stimulation of the uterus inanimal tests. They can, therefore, be used in the control of uterinebleeding, symptoms of menopause, threatened abortion and the like.

A preferred group of compounds may be represented by the formulae:

0 H: N/ I 2 0 O H C H:

and

'allgyl substituted by carbamyl, in which lower alkyl contains from oneto seven, primarily from one to four, carbon atoms, cycloalkylcontaining from three to seven,

particularly from five to six, ring carbon atoms, monocyclic carbocyclicaryl-lower alkyl, particularly phenyllower alkyl, in which lower alkylcontains from one to seven, particularly from one to four, carbon atoms,

monocyclic monoheterocyclic-lower alkyl, particularly twelve carbonatoms, particularly of a lower alkanoic acid containing from one toseven, particularly from one to four, carbon atoms, OH(R in which R,stands for lower alkyl containing from one to four carbon atoms,

lower alkenyl containing from one to four carbon atoms or lower alkynylcontaining from one to four carbon atoms, OAc'(R in which R, and Ac havethe previously given meaning, or :0, and R stands for hydrogen orhydroxy, therapeutically acceptable acid addition salts or lower alkylthereof.

This group of compounds may be represented by the compounds of theformulae:

quaternary ammonium compounds in whichvR" represents lower alkyl,containing from one -to seven, particularly-from one to four, carbonatoms,

cycloalkyl containing from five to six ring carbon atoms, phenyl-loweralkyl, in which lower alkyl contains from one to four carbon atoms, orpyridyl-lower alkyl, in which' lower alkyl contains from one to fourcarbon atoms, R stands for OH(H), OH(lower alkyl), in which lower alkylcontains from one to four carbon atoms, O'H(lower alkenyl), in whichlower alkenyl contains from one to four carbon atoms, OH(1ower alkynyl),in which lower alkynyl contains from one to four carbon atoms, or =0,the therapeutically acceptable mineral acid addition salts and the loweralkyl quaternary ammonium halides, sulfates and sulfonates thereof.

mula;

V V H H1 fill in which R" has the previously given meaning, 3'-R"- 2',4'dihydro 17a ethynyl 17ft hydroxy l,3,5()- estratrieno[2,3e]:1',3-oxazines of the formula:

rw-N Hu l in which R has the previously given meaning are specificgroups of compounds with outstanding estrogenic activities. In the aboveformulae R" stands primarily for four carbon atoms, cycloalkyl,containing preferably a from five to sixjriug carbon atoms, andphenyl-lower' alkyl, in which lower alkyl contains preferably from oneto four carbon atoms.

1,35,5(10)-estratrieno[3,4-e] l','3-oxazines' of a the forpolyalkyleneglycols or any other known carrier for medicaments. The pharmaceuticalpreparations maybe inrthe solid form, for example, as capsules, tablets,dragees and the like, or ,in liquid form, for example, as solutions,suspensions, emulsions and the like. If desired, they may-containauxiliary substances such as .preserving, stabilizing, wetting,emulsifying agents and the 1 like, salts for varying the osmoticpressure, buffers, or

no lower alkyl, such as lower alkyl containingtfrom oneto 7' The newcompounds of this invention may be used as 'rnedicaments in the form ofpharmaceutical preparations,

which contain the new compounds, the salts or the quaternary ammoniumcompounds thereof in admixture with a pharmaceutical organic orinorganic, solid or liquid carrier. 'For making up the preparationsthere can be employed substances which do not react with the newcompounds, such as water, gelatine, lactose, starches,

stearic acid, magnesium stearate, stearyl alcohol, talc, vegetableoils,benzyl alcohols, gums, propylene glycol,

other, auxiliary substances.

The compounds of the present invention may also be used oninter-mediates for the preparation of other useful compounds.

The compounds .of the present invention may be prepared, for example, byreactingone of the compounds of the formula:v

and

in which R has the above-given meaning, and with at least two equivalentamounts of formaldehyde or a re active derivative thereof, and, ifnecessary, separating a resulting mixture of compounds into singlecompounds and/or, if desired, converting a resulting salt into the freecompound and/or, if desired, converting a resulting compound into a saltor. quaternary ammonium com-' pound thereof.

' The reaction is preferably carried out in the presence of diluents,particularly water-miscible, polar solvents, for example, alcohols, suchas lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol andthe like, others, e.'g. ,tetrahydrofuran, p-.dioxane, diethyleneglycoldimethylether and the like, ketones, e.g. acetone, ethyl methyl ketoneand the like, 'carboxylic acid amides, e.g. formamide,N,N-dimethylformamide and the like, or water or mixtures of suchsolvents, as well as less polar solvents, such as aliphatichydrocarbons, e.g. pentane, hexane and the like, carbocyclic arylhydrocarbons, e.g. benzene, toluene and the like, or any other suitablesolvents.

Usually the amine and the phenol are given to the solution of theformaldehyde, which may be used as an aqueous solution thereof, or inthe form of a polymer thereof, e.g. para-formaldehyde, trioxymethyleneand the like, or'of an acetal thereof with a lower alkanol, e.g.methanol, ethanol and the'like, such as a di-lower alkoxymethane, e.g.dimethoxymethane, diethoxymethane and the like. The reaction may becarried out in the presence I of a condensing reagent, for example, abase, such as an alkali metal hydroxide, e. g. lithium hydroxide, sodiumhydroxide, potassium hydroxide, and the like. If necessary, the reactionmixture maybe heated, for example,

9 on the steam bath to about 80-90", if desired, in the atmosphere of aninert gas, e.g. nitrogen.

The resulting benzoxazine compound may crystallize upon cooling, or itmay be isolated, for example, by diluting the solution with a solventdiffering from the one used during the reaction and, if necessary,extracting the product, or by evaporating the solution and crystallizingthe residue. The reaction product is purified according to knownmethods, for example, by crystallization, recrystallization, adsorption,for example, or aluminum oxide, or another suitable adsorbent, andelution, or any other suitable purification method.

A resulting mixture of compounds may be separated on the basis ofphysico-chemical differences, such as solubility differences;crystallization from solvents or solvent mixtures, or any other suitableseparation method may be used.

The starting materials used in the above reaction are known, or if new,may be prepared according to known procedures. I

The compounds of this invention can be obtained in the form of the freebases was the salts thereof. A salt may be converted into the free base,for example, by reaction with an alkaline reagent, such as an alkalimetal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkalimetal carbonate, e.g. sodium or potassium carbonate or hydrogencarbonate, or ammonia, or with an anion exchange resin. A free base maybe converted into its therapeutically useful acid addition salts byreaction with one of the inorganic or organic acids outlinedhereinbefore; for example, a solution of the free base in a solvent,such as a lower alkanol, e.g. methanol, ethanol, propahol, isopropanoland the like, a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene,toluene and the like, an ether, e.g. diethylether and the like, ahalogenated aliphatic hydrocarbon, e.g. methylene chloride and the likeor in a mixture of solvents may be reacted with the acid or a solutionthereof and the desired salt may then be isolated.

Quaternary ammonium derivatives of the compounds of this invention maybe obtained, for example, by re acting the tertiary base with an esterformed by an alcohol and a strong inorganic or organic acid. Such acidsare more especially mineral acids, e.g. hydrochloric, hydrobromic,hydriodic, sulfuric acid and the like, or

bocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate and the like.The quaternizing reaction may be performed in the absence or in thepresence of a solvent, for example, a lower alkanol, e.g. methanol,ethanol, propanol, isopropanol, butanol, pentanol and the like, a loweralkanone, e.g. acetone, methyl ethyl ketone and the like, an organicacid amide, e.g. formamide, dimethylformamide and the like, a monocycliccarbocyclic aryl hydrocarbon, e.g. benzene and the like, a halogenatedhydrocarbon, e.g. methylene chloride and the like,- an ether, e.g.diethyl ether and the like, or any other equivalent solvent.

Quaternary ammonium compounds obtained may be converted into thecorresponding quaternary ammonium hydroxides, for example, by reacting aquaternary ammonium halide with silver oxide, or a quaternary ammoniumsulfate with barium hydroxide, by treating a quaternary ammonium saltwith an anion exchanger, or by electrodialysis. From any resultingquaternary ammonium base there may be prepared therapeutically suitablequaternary .45 strong organic acids, e.g. p-toluene sulfonic acid andthe This solution (Woelrn, basic, activity II); the column is developedwith which melts at l00-101 from the aboves olvent.

by treatment with hydrochloric acid in anhydrous methanol. Quaternaryammonium compounds may also crystallize as the hydrates; monoorpoly-quaternary ammonium compounds may be formed depending on the numberof tertiary amino groups.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any stage of" the process isused as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferablyu'sed'which lead to final products mentioned in'the beginning aspreferred embodiments of the invention;

The following examples are intended -;-to illustrate the invention andare not to be construed as being limitations thereon, Temperatures aregiven in degrees centigrade.

" Example 1 Tea cold solution of 0.65 g. of trioxymethylene and .a traceof potassium hydroxide in 35 ml. of n-propanol is added 1.1 g. ofbenzylamine, followed by 3.0 g. of 17u-ethynyl-estradioL. The mixture isrefluxed for fifteen hours under an atmosphere of nitrogen, the solventis I evaporated under reduced pressure and the residue is dissolved in a2:1-mixture of benzene and petroleum ether. is chromatographed onaluminum oxide the initial solvent mixture to yield 2.8 g. of crudematerial. The latter is dissolved in a mixture of methylene chloride andheptane, which is gradually evaporated until crystallization occurs. Atotal of 1.4 g. of crystalline product is filtered 011?, which isrecrystallized from the methylene chloride-heptaue mixture to yield 1.1g. of 3 benzyl 2.,4' dihydro 17a ethynyl 17Bhydroxy-1,3,5(10)-estratrieno[2,3-e]-1',3'-oxazine of the formula:

:'--- ozon after repeated recrystallizations Paper chromatography on W1-.paper, treated with a 121- ture of formamide and methanol containingone per cent of benzoic acid, shows Rf=25 in mobilephase A (chloroformsaturated with formamide) and Rf=50 in mobile phase B (lzl-mixture ofbenzene and chloroform, containing two percent of pyridine); thecompound is detected by treatment of the paper with antimony trichlorideor platinum hexachloride.

After removal of the previously mentioned 1.4 g. of crude crystallizate,the filtrate is further evaporated and 0.4 g. of 3'-benzyl-2,4dihydro17a ethynyl-l7/9-hy- .11 drew-15,5110Lestratrieno [3 ,4-e] 1 ,3'-oxazine of the formula: V

i Egg is recovered in amorphous form; paper chromatograph on theabove-mentioned paper shows Rf=90 in mobile phase A and Rf='85 in mobilephase B.

Example 2 A total of 1.0 g. :of cyclohexylamine'is added to a coldsolution of 0.65 g. of trioxymethylene and a trace of potassiumhydroxide in 35 ml. of propanol, which is followed by 3L0 gLof 17a-ethynyl-estradio1. The reaction mixture is refluxed for fifteen hoursunder an atmosphere of nitrogen, md worked up .as shown in Example 1.The initial eluate from the chromatogram yields 3.3 g. of

crude material, which 'is dissolved in cyclohexane and rechromatographedon 50 g. of a magnesia silica gel prep- .aration as described in-U;S.Patent No; 2,393,625 The .first fractions are crystallized from heptanegiving 0.59 g. :of crystalline material, 0.33 -g. :of a gummycrystalline product and 0.74. g. of .amorphousmaterial; an additionalamount of 0.521 g. of amorphous material is obtained-by -further;elution'with a lzl-mixture ofbenzene and cyclohexane. The initialcrystalline material is recrystallized from .heptane to yield the3'-cyclohexyl-2',4'-dihydro- 17a ethynyl-17B hydroxy 1,3,5(10)-'estratrieno- [3,4 e]-1",3'-oxazine of the formula! melting at 141-143; Rf=35 in mobile phase A (see Example 1).

The above-mentioned amorphous material-is combined and reprecipitatedfrom heptane yielding 1.2 g. of 3-cyclo- 'hexyl 2',4' dihyclro 17aethynyl 17B hydroxy- 1,3,5 (10)-estratrieno[2,3-e]-1',3-oxazine of theformula:

. .7 -12 V with an Rf= in mobile phase A (see Example 1) and Rf=30 inmobile phase B (see Example 1).

Example 3 To a cold solution of 0.65 g. of trioxymethylene and a traceof potassium hydroxide in 35 ml. of n-propanol is added 1.22 g.of'Z-phenylethylamine, followed by 3.0 g. of l7a-ethynyl-estradiol. Thereaction mixture is treated and worked up as shown in- Example 1. Thefirst eluate fractions of the chromatogram yields 2.2 g. of material,

which is dissolved in methylene chloride; the solution is slowlyevaporated until crystallization occurs. 0.38 g. of2,4'-dihydro-l7a-ethynyl 17ft hydroxy-3'-(2-phenylethyl) -l,3,Sl0)-estratrieno[3,4-e]l ,3'-oxazine of the formula -ozon is recoveredand .melts at 141-142 after repeated recrystallization; Rf=40 in mobilephase B (see Example 1.).

The methylene chloride filtrate after the removal of the crystallinematerial yields 1.8 g. of the amorphous 2,4"- dihydro- 17a ethynyl 175hydroxy 3 (2- V phenylethyl) -.1,3,5(10) estr'atrieno[2,3 e] 1,3'oxazine of the formula:

estratrieno [2,3 -e] -1-,3'-oxazine, V 2,4'-dihydro-3 '-isopropyl-1,7/3-propionyloxy-1 ,3 ,5 10) estratrieno[3,4-e}-1',3 oxazine,

Example 4 A trace of potassium hydroxide and 0.3 g. of trioxymethyleneare dissolved in 2 ml. of methanol, the solution is cooled in ice and0.15 g. of methylamine in 10 ml. of methanol is added, followed by 1.3g. of equilenin and 75 ml. of methanol. The reaction mixture is allowedto stand at 20 and then refluxed for two hours under an atmosphere ofnitrogen; after cooling, the crystalline material is filtered off andrecrystallized from a mixture of methylene chloride and ethanol to yield1.2 g. of 2',4'- dihydro-3-methyl-17-oxo-1,3,5(10),6,8 estrapenteno[3,4-e]-1,3'-oxazine of the formula:

which melts at 190-192".

0.5 g. of 2,4'-dihydro-3-methyl-17-oXo-1,3,5(10),6,8-estrapenteno[3,4,-e]-1',3'-oxazine is dissolved in an excess of methyliodide, and the reaction mixture is allowed to stand at room temperaturefor several days. The methyl iodide is evaporated off to yield themethiodide of 2,4'- dihydro-3-methyl-17-oxo-1,3,5 10) ,6,8estrapenteno[3,4-

e] -1,3-oxazine.

0.3 g. of 2',4-dihydro-3'methyl-17-oXo-1,3,5(10),6,8estrapenteno[3,4-e]-1',3-oxazine is dissolved in benzene and hydrogenchloride gas is passed through the solution; the resulting2,4'-dihydro-3'-methyl-17-oxo-1,3,5(10),6,8-estrapenteno[3,4-e]-1',3'-oxazine hydrochloride precipitates and isfiltered off.

By selecting the appropriate starting materials and reacting themaccording to the previously shown procedure, the3-benzyl-2',4'-dihydro-17 oxo 1,3,5 (10),6,8estrapentaeno[3,4-e]-1,3-oxazine, M.P. 188-189", yield: 77 percent, the3-cyclohexyl-2',4' dihydro 17 oxo- 1,3,5(10),6,8-estrapentaeno[3,4-e]1,3' oxazine, M.P. 192193, yield: 84 percent, and the2,4'-dihydro-3'-(2- phenylet-hy1)-17-oxo-1,3,5(10),6,8-estrapentaeno[3,4 e]- 1',3'-oxazine, M.P. 148-149, yield: 84percent, can be obtained.

14 What is claimed is: v t 1. A member of the group consisting ofcompounds of the formulae:

in which R' represents a member of the group consisting of lower alkyl,lower alkyl substituted by carbo-lower alkoxy, lower alkyl substitutedby carbamyl, cycloalkyl, monocyclic carbocyclic aryl-lower alkyl andmonocyclic monoheterocyclic aryl-lower alkyl, R represents a member ofthe group consisting ofgroups of the formulae ,6-OH(a-H), B-OAC'(a-H),B-OH(-R ;8-OAc'(a-R and =0, in which formulae Ac represents the acylradical of a therapeutically acceptable carboxylic acid containing fromone to twelve carbon atoms, and R represents a member of the groupconsisting of lower alkyl, lower alkenyl and lower alkynyl, and R standsfor a member of the group consisting of hydrogen and hydroxy, andtherapeutically acceptable acid addition salts thereof and lower alkylquaternary ammonium compounds thereof.

2. 3'-R"-2,4'-dihydro-17ot ethynyl 17p hydroxy- 1,3,5(10)-estratrieno[2,3-e]-1,3'-oxazine, in which R" representsphenyl-lower alkyl.

3. 3-benzyl-2',4-dihydro-17u-ethynyl 17 3 hydroxy- 1,3,510)'-estratrieno [2,3-e]-1',3'oxazine.

4. 2',4'-dihydro-17a-ethynyl-17fi-hydroxy-3'-(2phenylethyl)-1,3,5(10)-estratrieno[2,3-e]-1,3'-oxazine.

5. 3'-R-2',4'-dihydro-17a ethynyl 17,8 hydroxy-1,3,5(10)-estratrieno[3,4-e]-1',3'oxazine, in which R representsphenyl-lower alkyl.

6. 3-benzyl-2,4'-dihydro-17u-ethynyl 17,8 hydroxy- 1,3,5 10)-estratrieno [3,4-e] -1',3-oxazine.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: